Solution-Draw a diagram of the predicted results | Homework Helpers

Michaellis 10-year-old black male child who was admitted to the hospital because he was experiencing severe chest pain. He had been hospitalized on several previous occasions for vasoocclusive episodes that caused him to experience severe pain that could not be managed with nonprescription drugs such as ibuprofen. He was slightly jaundiced, short of breath and easily tired, and feverish. A chest x-ray was taken and was abnormal. An arterial blood sample showed a pO2 value of 6 kPa (normal is 10-13 kPa).

1. You suspect that Michael has sickle cell anemia and you have ordered an isoelectric focusing electrophoretic analysis of the chil’s lysed red blood cells. (Lysing the red blood cells releases the hemoglobin.) Draw a diagram of the predicted results. Why will this test allow you to diagnose this child’s disease?

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2. In the emergency room, oxygen (100%) was administered to the patient. (Inspired air normally is about 20% oxygen.) Why was this an effective treatment?

3. You recall reading in the medical literature about a dramatic new drug treatment for sickle cell anemia, and you’d like to try it on this patient. The drug is hydroxyurea, and is thought to function by stimulating the afflicted person’s synthesis of fetal hemoglobin. Exactly how hydroxyurea stimulated fetal hemoglobin synthesis is unclear, but it is believed that hydroxyurea is metabolized to Nitric Oxide (NO), which binds to a soluble guanylate cyclase enzyme which catalyzes the synthesis of a second messenger, cyclic GMP (cGMP). The cGMP interacts with transcription factors in a manner that is not completely understood to induce the transcription of the fetal hemoglobin gene.

a. In a clinical study, patients who took hydroxyurea showed a 50% reduction in frequency of hospital admissions for severe pain, and there was also a decrease in the frequency of fever and abnormal chest x-rays. Why would increasing the synthesis of fetal hemoglobin result in alleviating the symptoms of sickle cell anemia?

b. Medical practioners who used hydroxyurea as a treatment for sickle cell anemia noted that their patients seemed to benefit from the administration of the drug long before the synthesis of fetal hemoglobin had time to take effect. It has recently been determined that hydroxyurea can react directly with the iron ion of oxy- and deoxyHb to form iron nitrosyl hemoglobin (HbNO). Why would this be of benefit to the sickle-cell anemic patient?

c. In aIDition, hydroxyurea has been shown to produce NO directly, in less than an hour after hydroxyurea administration. It’s also possible that HbNO could produce free NO, either directly or indirectly. NO is an mportant second messenger which, even in nanomolar amounts, stimulates vasodilation. How could production of NO help the sickle-cell anemic patient?

4.A year ago, at a conference, one of your colleagues told you that she had “cured” a patient of sickle cell anemia by performing a bone marrow transplant. Why would this procedure “cure” sickle cell anemia?

5. At the same conference, you attendedaa talk describing the discovery of a novel mode of action of NO: NO might be involved in oxygen delivery to the cells in a more direct manner-through reacting with hemoglobin, for example. This hypothesis was confirmed when the investigators showed that NO can react with hemoglobin to form S-nitrosohemoglobin. The NO reacts with the sulfhydryl group on Cys93 on the ? chain of hemoglobin to form the S-nitrosohemoglobin. The reaction is readily reversible, with SNO-Hb releasing NO under certain conditions.

a. A purified sample of hemoglobin is subjected to a chemical modification experiment in which an alkylating agent is aIDed to the hemoglobin. The alkylating agent Nethylmaleimide (NEM) reacts with sulfhydryl groups as shown in Fig. 1. The NEM has the ability to react with the Cys ?93 in oxy-Hb but not deoxy-Hb.

What does this tell you about the environment of Cys ?93?


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